The present invention relates to novel phenyl- and pyridyl-tetrahydropyridines, to pharmaceutical compositions containing them, to a process for preparing them and to synthetic intermediates in this process.
U.S. Pat. Nos. 5,118,691 and 5,620,988 disclose tetrahydropyridines substituted with a 3-quinolylalkyl radical, which show dopaminergic activity.
It has now been found that certain tetrahydropyridines substituted with a quinolinylalkyl or isoquinolylalkyl radical have powerful activity with respect to modulating TNF-alpha (tumour necrosis factor).
TNF-alpha is a cytokine which has recently aroused interest as a mediator of immunity, of inflammation, of cell proliferation, of fibrosis, etc. This mediator is present in abundance in inflamed synovial tissue and exerts an important role in the pathogenesis of autoimmunity (Annu. Rep. Med. Chem., 1997, 32:241-250).
Thus, according to one of its aspects, the present invention relates to tetrahydropyridines of formula (I): 
in which
X represents N or CH;
R1 represents a hydrogen or halogen atom or a CF3 group;
R2 and R3 independently represent a hydrogen atom or a methyl group;
n is 0 or 1;
A represents a group of formula (a) or (b) 
xe2x80x83in which
R4 represents a hydrogen or halogen atom, a (C1-C4) alkyl group, a CF3 group, an amino group, a mono(C1-C4) alkylamino group or a di (C1-C4) alkylamino group;
R5 represents a hydrogen or halogen atom, a (C1-C4) alkoxy group, a (C1-C4) alkyl group or a CF3 group;
R6 represents a hydrogen atom, a (C1-C4)alkyl group or a (C1-C4)alkoxy group;
as well as the salts or solvates thereof.
In the present description, the term xe2x80x9c(C1-C4)alkylxe2x80x9d denotes a monovalent radical of a saturated straight-chain or branched-chain C1-C4 hydrocarbon.
In the present description, the term xe2x80x9chalogenxe2x80x9d denotes an atom chosen from chlorine, bromine, iodine and fluorine.
Preferred compounds are those in which n is zero.
Other preferred compounds are those in which R2 and R3 are hydrogen.
Other preferred compounds are those in which R1 is a CF3 group.
Other preferred compounds are those in which R1 is a fluorine atom.
Other preferred compounds are those in which X is CH and R1 is in position 2 or 3 of the benzene.
Other preferred compounds are those in which X is CH and R1 is a CF3 group.
Other preferred compounds are those in which X is a nitrogen atom and the pyridine is substituted in positions 2 and 6.
According to the present invention, the compounds of formula (I) can exist as N-oxide derivatives. As indicated in the above formula, the compounds of formula (I) can in particular bear the N-oxide group on the tetrahydropyridine or on the quinoline or the isoquinoline of the group A, or alternatively two N-oxide groups may be simultaneously present.
The salts of the compounds of formula (I) according to the present invention comprise both the addition salts with pharmaceutically acceptable inorganic or organic acids such as the hydrochloride, hydrobromide, sulphate, hydrogen sulphate, dihydrogen phosphate, citrate, maleate, tartrate, fumarate, gluconate, methanesulphonate 2-naphthalenesulphonate, etc., and the addition salts which allow a suitable separation or crystallization of the compounds of formula (I), such as the picrate or oxalate, or the addition salts with optically active acids, for example camphorsulphonic acids and mandelic acids or substituted mandelic acids.
The optically pure stereoisomers, and the mixtures of isomers of the compounds of formula (I), due to the asymmetric carbon, when either R2 or R3 is a methyl and the other is a hydrogen, in any proportion, form part of the present invention.
The compounds of formula (I) can be synthesized by a process which involves
(a) reacting the compound of formula (II): 
in which X and R1 are defined as above, with a functional derivative of the acid of formula (III): 
in which R2, R3, n and A are as defined above,
(b) reducing the carbonyl group of the compound of formula (IV) thus obtained: 
(c) dehydrating the intermediate piperidinol of formula (V) thus obtained: 
(d) isolating the compound of formula (I) thus obtained and optionally converting it into a salt or solvate thereof or into the N-oxide derivatives thereof.
The reaction in step (a) can be suitably carried out in an organic solvent at a temperature of between xe2x88x9210xc2x0 C. and the reflux temperature of the reaction mixture.
It may be preferable to perform the reaction without heating when it is exothermic, such as in the case in which the chloride is used as functional derivative of the acid of formula (III).
Suitable functional derivatives of the acid of formula (III) which can be used are the free acid, optionally activated (for example with BOP=tris(dimethylamino)benzotriazol-1-yloxyphosphonium hexafluorophosphate), an anhydride, a mixed anhydride, an active ester or an acid halide, preferably the bromide. Among the active esters, the one which is particularly preferred is the p-nitrophenyl ester, but the methoxyphenyl, trityl and benzhydryl esters and the like are also suitable.
The reaction solvent preferably used is a halogenated solvent such as methylene chloride, dichloroethane, 1,1,1-trichloroethane, chloroform and the like, but other organic solvents that are compatible with the reagents used, for example dioxane, tetrahydrofuran or a hydrocarbon such as hexane, can also be used.
The reaction may be carried out conveniently in the presence of a proton acceptor, for example an alkaline carbonate or a tertiary amine such as triethylamine.
The reduction in step (b) can be carried out conveniently using suitable reducing agents such as borane complexes, for example dimethyl sulphide/borane ([CH3]2Sxe2x80x94BH3), aluminium hydrides or a lithium aluminium hydride complex in an inert organic solvent at a temperature of between 0xc2x0 C. and the reflux temperature of the reaction mixture, according to the usual techniques.
The expression xe2x80x9cinert organic solventxe2x80x9d means a solvent which does not interfere with the reaction. Such solvents are, for example, ethers, such as diethyl ether, tetrahydrofuran (THF), dioxane or 1,2-dimethoxyethane.
According to one preferred procedure, the process is performed with the dimethyl sulphide/borane used in excess relative to the starting compound (II), at the reflux temperature, optionally under inert atmosphere. The reduction is normally complete after a few hours.
The dehydration in step (c) is readily carried out, for example, using an acetic acid/sulphuric acid mixture, at a temperature of between room temperature and the reflux temperature of the solvent used.
According to a preferred method, the reaction in step (c) is carried out in an acetic acid/sulphuric acid mixture in a ratio of 3/1 by volume, by heating to a temperature of about 100xc2x0 C. for 1-3 hours.
The desired compound is isolated according to the conventional techniques in the form of free base or a salt thereof. The free base can be converted into one of its salts by simple salification in an organic solvent such as an alcohol, preferably ethanol or isopropanol, an ether such as 1,2-dimethoxyethane, ethyl acetate, acetone or a hydrocarbon such as hexane.
The compound of formula (I) obtained is isolated according to the usual techniques and optionally converted into a salt or solvate thereof or into the N-oxide derivatives thereof.
The compounds of formula (I) can also be prepared by a coupling/reduction reaction starting with a compound of formula (VI): 
in which X and R1 are as defined above, with an aldehyde of formula (VII): 
in which R2, R3, n and A are as defined above, isolation of the compound of formula (I) and optional conversion into a salt or solvate thereof or into the N-oxide derivatives thereof.
The coupling/reduction reaction is carried out by mixing the starting compounds (VI) and (VII) in an organic solvent such as an alcohol such as for example, methanol, in acidic medium, in the presence of a reducing agent such as sodium cyanoborohydride, according to the conventional methods.
The starting compounds of formulae (II), (III) and (VI) are known or else can be prepared in an analogous manner to that of the known compounds. Such products are described, for example, in WO 97/01536; J. Am. Chem. Soc., 1948, 70:2843-2847; J. Med. Chem., 1997, 40 (7):1049.
The compounds of formulae (IV), (V) and (VII) are novel compounds and constitute a further aspect of the present invention.
The compounds of formula (VII) can be prepared by heating the trifluoromethylsulphonyl derivative (also known as xe2x80x9ctriflatexe2x80x9d) of a suitable hydroxy (iso)quinoline with N,N-dialkylethanolamine vinyl ether in the presence of a palladium catalyst and a strong base such as, for example, triethylamine, and by reacting the intermediate thus obtained with concentrated sulphuric acid, according to the usual procedures. Examples of such a process are reported in the experimental section. Alternatively, the compounds of formula (VII) can be prepared by reducing the corresponding acids of formula (III) according to the well-known methods.
The compounds of formula (I) bearing an N-oxide group on the nitrogen atom of the quinoline or of the isoquinoline can be prepared from the N-oxide derivatives of the compounds of formula (III) or (VII). Examples of such syntheses are given in the experimental section.
The compounds of formula (I) bearing an N-oxide group on the nitrogen atom of the tetrahydropyridine can be prepared by oxidation of the corresponding compounds of formula (I). In this case, the compound of formula (I) as obtained by the above syntheses is subjected to an oxidation reaction according to the conventional methods, for example to a reaction with m-chloroperbenzoic acid in a suitable solvent, and isolated according to the usual techniques that are well known to those skilled in the art.
The compounds of the invention have advantageous properties with respect to the inhibition of TNF-xcex1.
These properties were demonstrated with the aid of a test aimed at measuring the effect of molecules on the synthesis of TNF-xcex1 induced in Balb/c mice by lipopolysaccharide (LPS) from Escherichia Coli (055:B5, Sigma, St. Louis, Mo.).
The test products are administered orally to groups of 5 female 7- to 8-week old Balb/c mice (Charles River, France). One hour later, the LPS is administered intravenously (10 xcexcg/mouse). The blood of each animal is taken 1.5 hours after the administration of the LPS. The samples are centrifuged and the plasma is recovered and frozen at xe2x88x9280xc2x0 C. The TNF-xcex1 is measured using commercial kits (R and D, Abingdon, UK).
In this test, representative compounds of the invention were found to be very active, by inhibiting the synthesis of TNF-xcex1 even at very low doses.
By virtue of this activity and their low toxicity, the compounds of formula (I) and the salts or solvates thereof can be used in the treatment of diseases associated with immune and inflammatory disorders or as analgesics. In particular, the compounds of formula (I) can be used for treating atherosclerosis, autoimmune diseases, diseases entailing demyelinization of the neurons (such as multiple sclerosis), asthma, rheumatoid arthritis, fibrotic diseases, pulmonary idiopathic fibrosis, cystic fibrosis, glumerulonephritis, rheumatoid spondylitis, osteoarthritis, gout, bone and cartilage resorbtion, osteoporosis, Paget""s disease, multiple myeloma, uveoretinitis, septic shock, septicaemia, endotoxic shock, graft-versus-host reaction, graft rejection, adult respiratory distress syndrome, silicosis, asbestosis, pulmonary sarcoidosis, Crohn""s disease, ulcerative colitis, amyotrophic lateral sclerosis, Alzheimer""s disease, Parkinson""s disease, disseminated lupus erythematosus, haemodynamic shock, ischaemic pathologies (myocardial infarction, myocardial ischaemia, coronary vasospasm, angina pectoris, cardiac insufficiency, heart attack), post-ischaemic reinfusion attacks, malaria, mycobacterial infections, meningitis, leprosy, viral infections (HIV, cytomegalovirus, herpesvirus), opportunistic infections associated with AIDS, tuberculosis, psoriasis, atopic dermatitis and contact dermatitis, diabetes, cachexia, cancer and radiation-mediated damage.
The compounds of formula (I) and the pharmaceutically acceptable salts and solvates thereof are preferably administered orally.
In the pharmaceutical compositions of the present invention for oral use, the active principle can be administered in unit administration forms, as a mixture with conventional pharmaceutical supports, to animals and human beings for the treatment of the abovementioned complaints. The appropriate unit administration forms comprise, for example, tablets, which may be splittable, gel capsules, powders, granules and oral solutions or suspensions.
When a solid composition in the form of tablets is prepared, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose or other suitable materials or alternatively they can be treated such that they have sustained or delayed activity and such that they release a predetermined amount of active principle continuously.
A preparation in the form of gel capsules is obtained by mixing the active ingredient with a diluent and pouring the mixture obtained into soft or hard gel capsules.
A preparation in the form of syrup or elixir can contain the active ingredient together with a sweetener, preferably a calorie-free sweetener, methylparaben and propyl paraben as antiseptic agents, as well as a flavouring and a suitable colorant.
The water-dispersible powders or granules can contain the active ingredient as a mixture with dispersants or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or flavour enhancers.
The active principle can also be formulated in the form of microcapsules, optionally with one or more supports or additives.
In the pharmaceutical compositions according to the present invention, the active principle can also be in the form of an inclusion complex in cyclodextrins, or ethers or esters thereof.
The amount of active principle to be administered depends, as always, on the degree of progress of the disease as well as the age and weight of the patient. Nevertheless, the unit doses generally comprise from 0.001 mg to 100 mg, better still from 0.01 mg to 50 mg and preferably from 0.1 mg to 20 mg, of active principle, advantageously from 0.5 mg to 10 mg.
According to another of its aspects, the present invention relates to a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and at least one compound chosen from immunosuppressants, such as interferon beta-1b; adrenocorticotropic hormone; glucocorticoids such as prednisone or methylprednisolone; interleukin-1 inhibitors.
More particularly, the invention relates to a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and at least one compound chosen from roquinimex (1,2-dihydro-4-hydroxy-N,1-dimethyl-2-oxo-3-quinolinecarboxanilide), myloran (product from the company Autoimmune containing bovine myelin), antegren (monoclonal human antibody from the companies Elan/Athena Neurosciences) and recombinant interferon beta-1b.
Other possible combinations are those consisting of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a potassium-channel blocker such as, for example, fampridine (4-aminopyridine).
According to another of its aspects, the invention relates to a method for treating diseases associated with immune and inflammatory disorders as well as in the treatment of pain, in particular atherosclerosis, autoimmune diseases, diseases entailing demyelinization of the neurons (such as multiple sclerosis), asthma, rheumatoid arthritis, fibrotic diseases, pulmonary idiopathic fibrosis, cystic fibrosis, glumerulonephritis, rheumatoid spondylitis, osteoarthritis, gout, bone and cartilage resorbtion, osteoporosis, Paget""s disease, multiple myeloma, uveoretinitis, septic shock, septicaemia, endotoxic shock, graft-versus-host reaction, graft rejection, adult respiratory distress syndrome, silicosis, asbestosis, pulmonary sarcoidosis, Crohn""s disease, ulcerative colitis, amyotrophic lateral sclerosis, Alzheimer""s disease, Parkinson""s disease, disseminated lupus erythematosus, haemodynamic shock, ischaemic pathologies (myocardial infarction, myocardial ischaemia, coronary vasospasm, angina pectoris, cardiac insufficiency, heart attack), post-ischaemic reinfusion attacks, malaria, mycobacterial infections, meningitis, leprosy, viral infections (HIV, cytomegalovirus, herpesvirus), opportunistic infections associated with AIDS, tuberculosis, psoriasis, atopic dermatitis and contact dermatitis, diabetes, cachexia, cancer and radiation-mediated damage, comprising the administration of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, alone or in combination with other active principles.